tbuckley/cabot-search huggingface dataset:
Abstract 4449: The expression and immune regulation of thymic stromal lymphopoietin in non-small cell lung cancer development and progression
Authors: Chung-Yu Chen, Ying-Yin Chen, Hung-Chueh Peng, Yi-Ling Ye
Journal: Cancer Research (2023)

Abstract Purpose: Previous studies have shown thymic stromal lymphopoietin (TSLP) to be an important driver of type 2 inflammation. A new and unexpected function for TSLP has been found in the induction and progression of a variety of tumors. This study conducted TSLP performance in lung cancer patients and the correlation of the clinical pathological data. Materials and Methods: The patients with pathological diagnosis of lung cancer were enrolled. The percentage of CD19 + B cells was determined in the lymphocyte gate and counted via flow cytometry. Relevant serum cytokines including TSLP were analyzed using LEGENDplex software. In vitro study was conducted by A549 cell line and the mRNA expression change of TSLP was extracted by Reverse Transcriptase PCR (RT-PCR). Results: When comparing the frequencies of B cell subsets between early-stage (N = 31) and late-stage lung cancer group (N = 29), the frequency of memory B cell (17.3±6.1% vs 23.4±15.1%, p=0.042), CD27+IgM+ B cell (1.8±1.3% vs 2.9±2.3%, p=0.030), class-switched B cell (15.5±5.5% vs 22.2±14.9%, p=0.023), class-switched memory B cell (69.9±11.3% vs 59.9±19.7%, p=0.017) and plasmablast (8.5±7.3% vs 18.0±20.8%, p=0.019) were significantly different between groups. The patients with higher frequency of class-switched B cell had significantly worse prognosis than low frequency (HR 3.054, 95% CI 1.007-9.262, p=0.049). The level of IL-1B, IL-6, IL-10, IL-12, IL-13, and TSLP were significantly higher in the late-stage cancer patients. Simulation in vitro test with human lung A549 cell line was performed, the expression of short-form TSLP (sfTSLP) level decreased with the higher anti-cancer drug as Pemetrexed concentration. Conclusions: The increase proportion of CD27+CD38- (class-switched) B cell could be an independent, poor prognostic factor for NSCLC patients. TSLP signaling is addressed to the anti-cancer therapeutic response. Therefore, TSLP and relevant cytokines may be involved directly and indirectly in shaping the inflammatory status of the tumor microenvironment. Citation Format: Chung-Yu Chen, Ying-Yin Chen, Hung-Chueh Peng, Yi-Ling Ye. The expression and immune regulation of thymic stromal lymphopoietin in non-small cell lung cancer development and progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4449.
Abstract 5243: Functional characterization of genetic loci in basal cell carcinoma
Authors: Mingyue Li, Constance Turman, Peter Kraft, Jiali Han
Journal: Cancer Research (2023)

Abstract Background: Genome-wide association studies (GWAS) have identified over 30 loci associated with basal cell carcinoma (BCC) susceptibility. However, the causal variants and mechanisms at these loci remain unknown. We performed statistical fine mapping and functional enrichment to identify credible causal variants at 31 established BCC risk loci. Methods: We performed statistical fine mapping by applying the sum of single effects (SuSiE) method to a previously published GWAS from 12,945 BCC cases and 274,252 controls. To identify genomic annotations enriched for BCC-associated variants, we compared high Posterior Inclusion Probability (PIP) variants from SuSIE to low PIP variants: we performed multivariable logistic regression of high-PIP status on 17 variant annotations from the Functional Annotation of Variants Online Resources (FAVOR) database, including sequence-contextual and functional annotations. Results: We identified 6 variants with PIP&amp;gt;0.99: rs1126809 (TYR), rs1805007 (MC1R), rs78378222 (TP53), rs12203592 (IRF4), rs35407(SLC45A2 a.k.a. MATP), rs12916300 (HERC2). Five of these six variants are in pigmentation genes; the sixth is in the tumor suppressor TP53. At a seventh region, the 95% credible set contained two variants in or upstream of RALY, which has previously been shown to be associated with pigmentation traits and multiple non-skin cancers. Another four regions had fewer than 10 variants in the credible set; the median size of the credible set was 11 (range: 1-76). After adjusting for sequence context (including location relative to exons, introns, UTRs; GC content; local mutation density, and nucleotide diversity) variants in active chromatin regions (as determined from multi-tissue methylation marks), variants in transcription factor binding sites, and skin eQTLs were significantly more likely to be high-PIP variants. Conclusions: Our results identify candidate variants, genes, and mechanisms for further study in BCC carcinogenesis. Citation Format: Mingyue Li, Constance Turman, Peter Kraft, Jiali Han. Functional characterization of genetic loci in basal cell carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5243.
Abstract 6242: Inhibition of BIRC5/survivin by LQZ-7I inhibits neuroblastoma growth while hemizygosity of <i>BIRC5</i> does not: implications for therapy of neuroblastoma
Authors: Carmen Dorneburg, Celimene Galliger, Voker Rasche, Andre Lechel, Thomas F. Barth, Klaus-Michael Debatin, Christian Beltinger
Journal: Cancer Research (2023)

Abstract Overexpression of survivin, a crucial regulator of the mitotic spindle checkpoint, is associated with poor prognosis in neuroblastoma (NB). Transcriptional inhibitors of survivin have been tested in clinical trials. However, results have been disappointing. We thus investigated the small molecules LQZ-7I and S12 that inhibit dimerization of survivin protein and compared their growth-inhibiting efficacy with that of markedly decreased survivin expression in a novel transgenic NB mouse. Mice hemizygous for BIRC5 were crossed with TH-MYCN mice to generate BIRC5+/−/MYCNtg/+ mice. NB incidence, growth and retransplantation capacity were assessed. In vitro, LQZ-7I and S12 were used to inhibit survivin protein interactions and the effects on proliferation and cell cycle of NB cells were investigated. BIRC5 hemizygous mice developed NB although mRNA and protein expression of survivin was markedly decreased. Surprisingly, incidence and latency of the NB that developed in the BIRC5+/−/MYCNtg/+ mice did not differ from the NB in the TH-MYCN mice, and tumor growth and survival of the mice was not affected. In stark contrast, the survivin interaction inhibitors LQZ-7I and S12 abolished anchorage-independent growth and proliferation of NB cell lines. Reduced growth of NB cells resulted from defects in mitosis induced by LQZ-7I or S12 or. LQZ-7I was the more efficient inhibitor of NB cells while S12 was not able to reduce tumor growth in a xenograft model. Taken together, these results support the notion that inhibiting survivin interaction is more efficacious in NB than inhibiting survivin transcription. Citation Format: Carmen Dorneburg, Celimene Galliger, Voker Rasche, Andre Lechel, Thomas F. Barth, Klaus-Michael Debatin, Christian Beltinger. Inhibition of BIRC5/survivin by LQZ-7I inhibits neuroblastoma growth while hemizygosity of BIRC5 does not: implications for therapy of neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6242.
Abstract 1460: Co-expression network analysis reveals male breast cancer specific transcriptional module
Authors: Xuxu Gou, Junkai Wang, Jonathan T. Lei, Eric J. Jaehnig, Meenakshi Anurag
Journal: Cancer Research (2023)

Abstract Introduction: According to the American Cancer Society, An estimated 2,710 men are diagnosed with breast cancer annually of which about 530 die due to the disease annually in the United States. Most male breast tumors are estrogen receptor positive. Risk factors include age, radiation exposure, BRCA1/2 gene mutations, Klinefelter syndrome, testicular disorders, diabetes, gynecomastia (enlarged breast) etc. Due to low testing and incidence rate and lack of bioinformatics approaches focused on identification of drivers of rare cancer, little is known about this disease in men than in women. Because of this knowledge-gap there is no therapy that is specifically tailored for male breast cancer, leading to nineteen percent higher mortality in male than female with breast cancer. Method: In the past, gene expression analysis has revealed differential pathways in male than in female breast cancer, but these studies compared male and female tumors without considering innate (sex-specific) differences in the mammary tissues between the two sexes. To overcome these challenges, we have utilized publicly available tumor (E-TABM-810, TCGA-Breast) and normal (GTEX - mammary) datasets to identify pathways and gene co-expression networks enriched in specific transcription factor (TF) targets that are specific to male breast tumors . Findings from this analysis is further validated in male breast tumor patient derived xenograft (PDX) model. Result: Using differential pathway analysis corrected by sex, Type I diabetes mellitus is the only Hallmark pathway signature that is significantly downregulated in male tumors compared to both female tumors and normal mammary tissue. No pathway is distinctively up-regulated in male tumors. Co-expression network analysis of gene expression datasets identified unique TF-driven networks that are specific to male breast tumors. This analysis identified a network of ELK1 and DMRT1 TF targets that are unregulated and downregulated in male breast tumors respectively. This was further validated in PDX dataset. Conclusion: Based on our results, we hypothesize that loss of DMRT1 TF activity is potentially associated with occurrence of male breast tumors. The role of DMRT1 in sex differentiation and gonadal differentiation has been explored, but its role in male breast tumor formation is not as well characterized. Thus, our analysis provides novel insight in transcription factors associated with incidence of this rare form of cancer in men. Citation Format: Xuxu Gou, Junkai Wang, Jonathan T. Lei, Eric J. Jaehnig, Meenakshi Anurag. Co-expression network analysis reveals male breast cancer specific transcriptional module [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1460.
Abstract 1581: KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity with multiple PARP inhibitors in BRCA mutant cancers
Authors: Erica Tobin, Pamela Sullivan, Morgan Murray, Hugh Gannon, Anne Dodson, Sol Shenker, Frank Stegmeier, Andrew Wylie, Louise Cadzow
Journal: Cancer Research (2023)

Abstract Tumors harboring BRCA1/2 mutations and other homologous recombination deficiencies are sensitive to agents targeting pathways involved in DNA repair including poly (ADP-ribose) polymerase (PARP) inhibitors, which have been approved for the treatment of BRCA mutant cancers. Despite the clinical benefit with these drugs, many patients achieve incomplete disease control and often develop resistance. By employing our CRISPRomics® technology to screen over 600 cancer cell lines, we identified the deubiquitinating enzyme USP1 as one of the top targets that displays selective anti-tumor activity in ovarian and triple negative breast cancers with homologous recombination deficiencies. Subsequent drug discovery efforts identified KSQ-4279 as a potent and highly selective first-in-class small molecule USP1 inhibitor that is now in clinical development. In preclinical models, we previously demonstrated that KSQ-4279 shows therapeutic potential in combination with olaparib for treating patients who are either intrinsically resistant, or have developed acquired resistance to PARP inhibitors. We performed studies to investigate the therapeutic potential of combining KSQ-4279 across a variety of PARP inhibitors with different ‘PARP trapping’ potencies. Clonogenic assays demonstrated synergistic effects of KSQ-4279 across multiple PARP inhibitors regardless of their PARP trapping potency. Second generation PARP1 selective inhibitors such as AZD5305 are currently in clinical development and may provide a safety and efficacy advantage for patients. We have investigated the potential of combining KSQ-4279 with AZD5305 in a PARP refractory patient-derived triple negative breast cancer (TNBC) xenograft model by evaluating tolerability and anti-tumor efficacy. We observed significantly greater and more durable anti-tumor activity, including regressions, with the combination therapy compared to single agents. Our data supports the clinical testing of KSQ-4279 in combination with PARP inhibitors. Citation Format: Erica Tobin, Pamela Sullivan, Morgan Murray, Hugh Gannon, Anne Dodson, Sol Shenker, Frank Stegmeier, Andrew Wylie, Louise Cadzow. KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity with multiple PARP inhibitors in BRCA mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1581.
Abstract 2622: Targeting Rac/Cdc42 GTPases to overcome HER2-targeted therapy resistance
Authors: Miciely Cristal Aponte Reyes, Luis E. Velazquez Vega, Suranganie Dharmawardhane
Journal: Cancer Research (2023)

Abstract Breast cancer is the most common cancer in women. Breast cancer is categorized by the overexpression (or lack thereof) of estrogen receptors (ER+/-), progesterone receptors (PR+/-) or human epidermal growth factor 2 receptors (HER2+/-). Specifically, HER2+ breast cancer is one of the most aggressive subtypes, comprising ~20% of all cases. Overexpression of the HER2 receptor leads to active downstream signaling that results in cell proliferation and metastasis. Clinically, this problem has been tackled by targeting the HER2 receptor with antibodies (e.g., Trastuzumab, Pertuzumab) and (or) tyrosine kinase inhibitors (TKIs; e.g., Lapatinib). However, patients may present with intrinsic or acquired resistance to these therapies. Molecular mechanisms of resistance to HER2 targeted therapy include activating mutations, alterations in downstream effectors, and compensation from other growth factor receptors. The active signaling sequelae from such mechanisms converge on the activation of guanine nucleotide exchange factors (GEFs) that regulate the GTPases Rac and Cdc42. These GTPases are critical for cell migration/invasion and have been correlated with poor prognosis in breast cancer patients. Therefore, targeting the activation of Rac/Cdc42 is a rational strategy to overcome HER2-targeted therapy resistance. Previously, we characterized the dual Rac/Cdc42 inhibitor MBQ-167 with IC50s of 103nM and 78nM for Rac and Cdc42, respectively. Our objective is to test MBQ-167 as an alternative to overcome HER2-targeted therapy resistance. To test the hypothesis that MBQ-167 will overcome HER2 therapy resistance, metastatic trastuzumab resistant HER2 overexpressing cells were treated with vehicle or individual or combined Trastuzumab and MBQ-167. Rac activity was determined by pulldown assays for active (GTP-bound) Rac, and viability was tested by MTT assays. Additionally, we measured apoptosis via caspase 3/7 activity and western blotted for the active signaling sequelae downstream of Rac. MBQ-167 reduced Rac activity and downstream signaling, as well as cell viability with a GI50 of 78nM after 72 hours, while caspase activity was increased after 24 hours of treatment. The results presented herein show the utility of the Rac/Cdc42 inhibitor MBQ-167 in overcoming HER2-targeted therapy resistance. Citation Format: Miciely Cristal Aponte Reyes, Luis E. Velazquez Vega, Suranganie Dharmawardhane. Targeting Rac/Cdc42 GTPases to overcome HER2-targeted therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2622.
Abstract 523: Targeting myc-amplified cancers with a novel prodrug inhibiting aurora A kinase
Authors: Ya-Hui Chi, Chun-Ping Chang, Teng-Kuang Yeh, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen, Yi-Yu Ke, Jing-Ya Wang, Ching-Ping Chen, Tsung-Chih Hsieh, Mine-Hsine Wu, Chiung-Tong Chen
Journal: Cancer Research (2023)

Abstract Upregulation of Aurora kinases has been associated with increased tumor progression, and thus they are appealing targets for the development of anti-cancer therapies. In addition to have a critical role in cell cycle regulation, Aurora kinases have been shown to stabilize MYC-family oncoproteins for the maintenance of malignancy. Aurora kinase inhibitors such as Alisertib has demonstrated compelling anti-tumor efficacies; however, the reported side effects including serious haematological disturbances have limited its risk-benefit ratio in clinical use. In this study we discovered a novel pyrimidine-based Aurora kinase inhibitor compound A that degraded MYC- and MYCN- oncoproteins with better potency than Alisertib. The acyl-based prodrug design leads to the discovery of compound B which was able to regress MYC- or MYCN- overexpressing tumor xenografts including small cell lung cancer, neuroblastoma, hepatocellular carcinoma and medulloblastoma using a once-a-week (QW) oral dosing regimen. Pharmacokinetic studies revealed that the tumor/plasma ratio of compound B was about 20 at 24 h post drug administration, and the active compound remained detectable in the tumors after 7 days. No significant haematological or liver/kidney biochemical aberration was observed in mice treated with up to 500 mg/kg of DBPR728 on a QW dosing regimen in a 21-day cycle. The unique pharmacokinetic and molecular properties of compound B hold potential clinical promise for treating MYC- and MYCN- amplified tumors with manageable on-target haematological adverse effects caused by Aurora kinase inhibition. Citation Format: Ya-Hui Chi, Chun-Ping Chang, Teng-Kuang Yeh, Wan-Ping Wang, Yen-Ting Chen, Chia-Hua Tsai, Yan-Fu Chen, Yi-Yu Ke, Jing-Ya Wang, Ching-Ping Chen, Tsung-Chih Hsieh, Mine-Hsine Wu, Chiung-Tong Chen. Targeting myc-amplified cancers with a novel prodrug inhibiting aurora A kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 523.
Abstract 2889: Novel subset of granulocytic MDSCs as immunosuppressive regulators and therapeutic targets in gastric cancer
Authors: Takumi Iwasawa, Suguru Yamauchi, Tetsu Fukunaga, Hajime Orita, Kazunori Kato
Journal: Cancer Research (2023)

Abstract The development and progression of cancers are frequently promoted by immunosuppressive cells, such as Treg and myeloid-derived suppressor cells (MDSCs) mediated by various immune checkpoint molecules. Recently, the immune checkpoint inhibitor anti-PD-1 neutralizing antibody has become available for the first-line treatment of gastric cancer (GC) in Japan. However, there is no correlation between PD-1 or PD-L1 expression in Treg or GC tissues and clinical responses to anti-PD-1 antibody. MDSCs are immature myeloid cells thought to suppress immune cell action, but the functional cell surface markers that define MDSCs correlated with cancer progression has not yet been clarified well. In this study, we identified a new subset of potential therapeutic and diagnostic targets for MDSCs in GC patients. Significantly higher levels of immune checkpoint molecules, PD-1 and PD-L1, were expressed on granulocytic MDSCs from advanced than early-stage of GC patients. Interestingly, we found that a subset of G-MDSCs expressed not only PD-1 but also PD-L1 and the pretreatment of G-MDSCs with anti-PD-1 antibody ameliorated T cell responses in vitro. We also found that G-MDSCs isolated from patients treated with anti-PD-1 antibody had a lower ability to suppress T cells. These data indicate that a novel subset of G-MDSCs expressing PD-1 found in advanced GC could be novel therapeutic targets. Citation Format: Takumi Iwasawa, Suguru Yamauchi, Tetsu Fukunaga, Hajime Orita, Kazunori Kato. Novel subset of granulocytic MDSCs as immunosuppressive regulators and therapeutic targets in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2889.
Abstract 5251: <i>Skeletonema marinoi</i> algae extract and carotenoid fucoxanthin are endowed with potential chemopreventive and angiopreventive properties for prostate cancer
Authors: Adriana Albini, Luana Calabrone, Douglas M. Noonan, Marco Festa, Cinzia Ferrario, Valentina Carlini, Debora Macis, Luigi Pistelli, Christophe Brunet, Clementina Sansone
Journal: Cancer Research (2023)

Abstract Background: Research and production of natural anti-oxidants is growing and is developed both in experimental laboratories and in nutraceuticals and pharmaceutical industries. Marine microorganisms represent underestimated sources of bioactive compounds endowed with anti-oxidant, anti-inflammatory, cardiovascular protective and anti-angiogenic properties, all beneficial effects on human health. Methods: Chemopreventive and anti-angiogenic activities of extracts from the marine coastal diatom Skeletonema marinoi (Sm) and carotenoid fucoxanthin, that is present in Sm, were evaluated in prostate cancer (PCa) and endothelial cell lines in in vitro. Morphogenesis assay was carried out to evaluate effects on HUVEC ability to form capillary-like structure on Matrigel. Gene expression analysis was performed by qPCR, measuring different inflammation and angiogenesis gene expression in cells treated with Sm extract and fucoxanthin. Membrane antibodies arrays were used to see alterations at protein level of pro- or anti-angiogenic factors. Results: Sm extract and fucoxanthin were able to decrease cell viability, in MTT and Crystal violet assays. Furthermore, we observed that fucoxanthin enhanced the effects of chemotherapeutic drugs, 5-Fluorouracil (5-FU) and cisplatin (Cis-Pt), two of the most commonly used anti-cancer drugs. Sm extract and fucoxanthin hindered vascular mimicry of PCa cells and also inhibited capillary structure formation in endothelial cells. Finally, Sm extract and fucoxanthin shown a down-regulation of inflammation and angiogenesis associated genes. Conclusions: Our study suggests promising potential chemopreventive and angiopreventive activities of Skeletonema marinoi extract and fucoxanthin for prostate cancer. Microalgae derived drugs can be a potential and relevant source of novel nutraceutical and preventive compounds, which can be considered as dietary supplements or in combination treatments in cancer prevention approaches. Citation Format: Adriana Albini, Luana Calabrone, Douglas M. Noonan, Marco Festa, Cinzia Ferrario, Valentina Carlini, Debora Macis, Luigi Pistelli, Christophe Brunet, Clementina Sansone. Skeletonema marinoi algae extract and carotenoid fucoxanthin are endowed with potential chemopreventive and angiopreventive properties for prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5251.